title: On the histone lysine methyltransferase activity of fungal metabolite chaetocin.
abstract: Histone lysine methyltransferases (HKMTs) are an important class of targets for epigenetic therapy. 1 (chaetocin), an epidithiodiketopiperazine (ETP) natural product, has been reported to be a specific inhibitor of the SU(VAR)3-9 class of HKMTs. We have studied the inhibition of the HKMT G9a by 1 and functionally related analogues. Our results reveal that only the structurally unique ETP core is required for inhibition, and such inhibition is time-dependent and irreversible (in the absence of DTT), ultimately resulting in protein denaturation. Mass spectrometric data provide a molecular basis for this effect, demonstrating covalent adduct formation between 1 and the protein. This provides a potential rationale for the selectivity observed in the inhibition of a variety of HKMTs by 1 in vitro and has implications for the activity of ETPs against these important epigenetic targets.
authors.affiliation: Department of Chemistry, Imperial College London , South Kensington Campus, London SW7 2AZ, United Kingdom.
authors.forename: Fanny L
authors.initials: FL
authors.lastname: Cherblanc
authors.forename: Kathryn L
authors.initials: KL
authors.lastname: Chapman
authors.forename: Jim
authors.initials: J
authors.lastname: Reid
authors.forename: Aaron J
authors.initials: AJ
authors.lastname: Borg
authors.forename: Sandeep
authors.initials: S
authors.lastname: Sundriyal
authors.forename: Laura
authors.initials: L
authors.lastname: Alcazar-Fuoli
authors.forename: Elaine
authors.initials: E
authors.lastname: Bignell
authors.forename: Marina
authors.initials: M
authors.lastname: Demetriades
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Schofield
authors.forename: Peter A
authors.initials: PA
authors.lastname: DiMaggio
authors.forename: Robert
authors.initials: R
authors.lastname: Brown
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Fuchter
mesh_terms: D002597:Chaetomium / Q000737:chemistry* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D011495:Histone-Lysine N-Methyltransferase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D008968:Molecular Conformation; D010879:Piperazines / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D011994:Recombinant Proteins / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D010879:Piperazines; D011994:Recombinant Proteins; C002511:chaetocin; D011495:Histone-Lysine N-Methyltransferase